3518
J.Org. Chern., Vol. 43, No. 18, 1978
Mathias and Overberger
Mass Spectral Behavior of 5(6)-Substituted Benzimidazoles L. J. Mathias and C. G. Overberger* Department of Chemistry and the Macromolecular Research Center, The University o f Michigan, A n n Arbor, Michigan 48109 Received November 14,1977
Three general classes of 5(6)-substituted benzimidazoles were compared according to common or similar fragmentation pathways in the mass spectrometer. The 5(6)-alkylderivatives fragment through a common intermediate of mle 131 as demonstrated by metastable ion ratios for the 2-13C-labeledcompounds. It is suggested that this intermediate possesses a ring-expanded structure resembling that of 1,3-diazaazulenewhose fragmentation behavior is very similar. For both species, competitive pathways exist for loss of the 2 carbon and carbocyclic ring carbons with HCN or CN. fragments. Moreover, the expected loss of the 2 carbon of the imidazole ring with these fragments is not the predominant process. The second general group of derivatives fragments by complete loss of the 5(6)substituent (NOz, C1, COzH, COCH3) to give a common ion of mle 117. Again, the metastable losses of HCN and H W N from the 2-’3C-labeled derivatives confirms the common structure of this ion and indicates predominant loss of carbocyclic ring carbons. Finally, the similar behavior of several 5(6)-alkenylbenzimidazolesimplies fragmentation through a common 143 ion which may result from a ring-expansion process similar to that of styrene. The three main fragmentation pathways observed here should be general for a variety of benzimidazole derivatives. More importantly, the metastable ratio technique for common ion identification is found to be much more reliable for 13C-labeledcompounds than for those with 2H labeling. Increased availability of 13C-enrichedreagents makes this technique one of broad applicability in mass spectral investigations. The application of mass spectrometry to the identification and structure determination of heterocyclic compounds has recently been experiencing explosive growth. For such application, the observation of straightforward fragmentation behavior general to a given class of heterocycles would be most desirable. Such is not often the case, however. A recent survey indicates that rearrangements and competitive fragmentation pathways are very common for heterocyclic compounds.1 These processes make difficult the understanding of the details of the mass spectral behavior. In this paper, we discuss the general and detailed behavior of several 5(6)-substituted benzimidazoles (structures I-XVI). Isotopic labeling is em-
xm> H
I, X 11, X 111, X VII, X VIII, X IX, X x, x XI, X XII, X XIII, X XIV, X XV, X XVI, X
I\‘
CH, CH,CH,OH CH,CH,Cl = CO,H = COCH, = NO, = = =
=
c1
CH(OH)CH, CH=CH, CH=CHCO,H CH=CHCO,CH, = CH=CHCO,CH,CH=CH, = CH=CHCONHCH,CH=CH, = = = =
V, Y = SH VI, Y = SH
ployed to indicate possible fragmentation mechanisms and probable intermediate structures. The techniques presented here are general and should be useful for indicating and establishing ionic structures and fragmentation pathways for other heterocycles. An extensive literature investigation of benzimidazoles revealed a paucity of mass spectral information despite widespread industrial and academic interest in this family of heteroaromatics.* Only recently, during the course of our
work, did reports appear concerning more detailed investigations of the parent b e n ~ i m i d a z o l e and ~ , ~ l-ethylbenzimi d a ~ o l eThis . ~ work supports our contention that common fragmentation pathways may exist for compounds which are structurally similar or even quite different. For example, for benzimidazole, indazole, and o-aminobenzonitrile (below), rearrangement of the molecular ions of all three compounds to a common structure is observed prior to fragmentation of the metastable i0ns.39~Our work with substituted benzimid-
azoles and related heterocycles indicates that extensive rearrangement to common structures probably occurs for many daughter ions as well as molecular ions. In this paper, extensive use is made of I3C labeling in the 2 position of benzimidazoles for two purposes. In our initial observations on unlabeled and 2H-labeled benzimidazoles, it was apparent that rearrangement processes and/or competitive fragmentations were occurring for many derivatives. It was necessary to determine whether either or both of these possibilities involved only hydrogen scrambling or if carbon atoms were involved as well in skeletal rearrangements. The second goal was to develop a technique involving the labeled carbon to confirm common ionic structures. This technique involves metastable ions and requires two or more competitive fragmentations of the ion suspected of a common structure. For two major groups of 5(6)-substituted benzimidazoles, common structures were found for the major daughter ions using this technique. In addition, skeletal rearrangements and competitive fragmentations were found to be quite extensive for all derivatives studied. The details of the fragmentation behavior are discussed in terms of general pathways and behavior. Three major groups were observed with classification made according to the most intense pathway. Of course, with heterocycles such as benzimidazoles, several competitive pathways may be observed for any given derivative and some of the more interesting and useful of the minor paths will be described on an individual basis.
Procedures The syntheses of several deuterium-labeled derivatives as well as the 2-W-labeled compounds are given in the Exper-
0022-326317811943-3518$01.00/0 0 1978 American Chemical Society
Mass Spectral Behavior of 5(6)-Substituted Benzimidazoles imental Section. The procedure developed for the latter was based on generality as well as conservation of the expensive carbon-13-containing reagent used. Phillip’s original synthesis of benzimidazoles6 employs ring closure of an aromatic or1ho diamine with a large excess of formic acid in refluxing 4 N hydrochloric acid. We found that only a slight excess of formic acid is necessary to give almost quantitative yields under similar conditions. Furthermore, rather than using commercially available [ 13C]formicacid, the much less expensive 130dium [13C]formatewas employed with in situ liberation of the acid. These two measures brought the cost of 2-13C-labeled benzimidazoles enriched to 90% down to ca. $30 per 200 mg sample. For replacement of exchangeable hydrogens with deuterium, prior exchange by recrystallization or reprecipitation from *H20 gave disappointing results. Reexchange of the deuterium in the sample with exchangeable hydrogens absorbed on the walls of the source is the probable explanation, since more than adequate time exists for ca. 50 collisions with the source walls before ionization takes place.7 This problem was o v w come by introducing a 2Hz0 slurry of the sample into the source on the solid probe. Repeated spectral scans were then made for several minutes after operating pressures were reached. The amount of exchangeable deuterium incorporated into the parent ions varied in a nonregular manner with time, and the spectrum or spectra with the highest isotope incorporation were employed. Deuterium exchange was routinemly increased to 90% or better with this method. The procedure presented here for the comparison of ionic structures in the mass spectrometer is based on two requirements. The ion under consideration must undergo two or more competitive fragmentations and each must exhibit a measurable metastable peak. The comparison is made of the ratio of intensities of the metastable peaks of the Competitive fragmentations. For ions of the same structure but from different parent or precursor species, the ratio of metastable intensities will be the The requirement of competitive fragmentations is generally satisfied by losses of fragments of different molecular weig b t and c o m p o s i t i ~ n . ~However, J~ with nitrogen-containing heteroaromatics such as benzimidazoles, almost all fragmentations involving the skeletal framework result in loss 3f HCN. The hydrogen, carbon, and nitrogen atoms lost with this fragment may come from different parts of the molecule, however. For example, in the scheme below, two possible intermediates for partial or complete “scrambling” of carbon atoms involved in HCN loss are presented. For structure A,
€3
it is possible that two mutually exclusive, competitive fragmentations occur which do not require prior rearrangement of the benzimidazole nucleus. Thus, fragments i and ii would involve completely different HCN molecules. The second possibility involves rearrangement of the nucleus prior to fragmentation, for example, to structure B or C. Structure :B might then lose HCN by competitive loss of fragments iii and iv. A further consideration is the energy of the species under consideration. Thus, for example, one can envision a situation where the ionic lifetime is comparable to the time required for rearrangement. Competitive losses of HCN could occur froin structure A via fragment i and from structure B via fragment iii. A priori, the presence of a *H or 13C label would not di!jtinguish among these three (and other) possibilities. However,
J.Org. Chem., Vol. 43, No. 18, 1978
3519
because of energetic requirements, it is possible to eliminate some of these possibilities from consideration. It is well known that ionization of molecules with 70 eV electrons results in molecular ions with a broad range of energies and lifetimes8 For our purposes, it is possible to break this distribution down into three general groups.8 First, those parent ions with insufficient energy to fragment before arriving at the detector are seen as molecular ions. Second, those parent ions with sufficient energy to fragment in the source are detected as daughter ions. (Qualitatively, the higher the initial ionic energy, the greater the probability of continued fragmentation to daughter ions of lower molecular weight.) Finally, parent ions with intermediate energies and lifetimes fragment between the source and the detector and are observed as metastable peaks. For each daughter ion, of course, similar energetic requirements again lead to observation of the daughter ion, a metastable ion, or a second daughter ion. Examining the processes discussed above for structures A and B, for example, it is possible to qualitatively relate the type of process with the relative energy and lifetime of the ion under consideration.12 That is, it has been observed that direct cleavage fragmentations, e.g., loss of i or ii from A, are favored at high energies. Rearrangement processes, e.g., to structure B or C, are favored a t lower energies and longer lifetimes. Thus, if competitive fragmentations are occurring from two different structures, e.g., i from A and iii from B, the former should be most evident with the stable (parent and daughter) ion peaks while the latter should predominate almost completely with metastable peaks. To rephrase, if rearrangement is taking place it will generally be complete on the time scale of the metastable peaks. This conclusion has been widely supported by experimental observations involving both alkanes and heteroatom-containing compounds.3~4~9-11~13~1* In almost all cases, rearrangement processes which were incomplete for stable ions were found to be complete for the longer lived metastables. An example of special interest involves the monodeuterated derivatives of benzimidazole, indazole, and o-aminobenzonitrile previously menti0ned.3,~For all three isomeric compounds, losses of HCN and 2HCN were competitive for both the stable and metastable ions. With the stable ions, the ratios of HCN to *HCN lost from the parent ions were widely different for the three compounds. However, the ratios of metastable peaks for these two losses were within experimental error for all three. The two conclusions which may be drawn from the identical isotopic metastable ratios are, first, that the competitive losses of HCN and *HCN involve rearrangement that may be incomplete for stable ions but complete for metastable ions; and second, the rearranged structures are identical for all three compounds. The obvious corollary to the former is that for the stable ions, fragmentation may be occurring from both the rearranged and unrearranged structures, the amount from each being somewhat dependent on how similar the common rearranged structure is to each of the three parent structures. In this paper, the confirmation of a common structure relies on the ratio of metastable peak intensities for the competitive losses of H13CN and H1*CN. While this would be a trivial comparison if no rearrangement processes were taking place and a single fragmentation mechanism were observed, such is definitely not the case for benzimidazoles. The a priori prediction for 2-unsubstituted benzimidazoles in general is that loss of HCN should involve the 2 carbon almost exclu~ive1y.l~ In fact, loss of carbocyclic carbons compares favorably or predominates for all the 2-labeled derivatives studied here.16 Thus, the 2-l3C label provides a means of confirming common structure as well as assisting in the elucidation of the nature of the rearranged structures and the types of compet-
3520 J. Org. Chem., Vol. 43, No. 18, 1978
Mathias and Overberger
'Table I. Summary of the Mass Spectral Behavior of 5(6)-Substituted Benzimidazoles registry no.
base ion (M= parent)
(VII) COzH
15788-16-6
155 M
1
(VIII) COCHB
58442-16-3
145
1
94-52-0 4887-82-5
163 M 152 M
2 2
66792-92-5
119
2
4070-35-3
144 M
3
(XIII) CH=CHCO:!H
51819-00-2
188 M
2
(XIV) CH=CHCO&H3
66792-93-6
202 M
2
(XV) CH=CHC02CHzCH=CH2
66792-94-7
171
2
(XVI) CH=CHCONHCHzCH=CHz
66792-95-8
171
2
614-97- 1 15788-11-1
132 M 131
2 2
14984-14-6
131
2
4887-83-6
132 M
2
M-OH-COHCN M - CH30 - CO - HCN M - CHz=CHCHzO - CO - HCN M - CHz-CHCHzNH - CO - HCN M - H - HCN M - CH20H HCN M - CHzCl HCN M - H - HCN
275-94-5 15852-41-2
130 M 162 M
2 2
M - HCN M - HCN
5(6)-substituent
(111) CHzCH&l
(V) DAA (VI) DAA-2-SH
Mno.of HCN pathsa
major path M - OH - CO - HCN M - CH3 - CO - HCN M - NO2 - HCN M - C1- HCN M - HCN - HCN M - CH3 - CO - HCN M - CzHz - HCN
ring exp.6
2Hc
I3Cd
no
synth. ref 6
no
117
117
e
no no
? ?
117 117
6 6
144? 143 143
144 143
23 27
143
e
143
e
143
e
131 131
131 131
131
131
6 28
28
131
131
131
6
no no
no no
no no
19 19
a Number of major, competitive fragmentation pathways at 70 eV. Ring expansion probable in the listed ions. 2H labeling indicates hydrogen scrambling in the ions listed. 13Clabeling indicates skeletal rearrangement in the ions listed. e New compounds.
For benzimidazole, then, the following conclusions can be drawn. Metastable ions, and perhaps most of the stable ions, have rearranged completely before fragmentation. This proResults a n d Discussion cess involves both the rearrangement of the carbon-nitrogen skeleton and scrambling of hydrogens on the imidazole ring Benzimidazole. The details of the fragmentation behavior with a limited number of hydrogens on the carbocyclic ring. of the parent benzimidazole will be discussed in a subsequent paper in relation to similar heterocycles. A few general obSeparate mechanisms probably exist for skeletal and hydrogen servations are important, however, for comparison with the rearrangcments. Competitive loss of labeled and unlabeled HCN may, therefore, result from partial scrambling of the behavior of the 5(6)-substituted derivatives described here. label (2H)and/or competitive mechanisms for fragmentation Both 2H and 13C labeling3 indicate that fragmentation of the parent ion occurs by competitive processes apparently ininvolving different atoms of the rearranged structure (13C and volving both unrearranged and rearranged structures. Rear2H). Evidence for the 5(6)-substitutedbenzimidazoles studied rangement is complete for metastable ions, although comhere indicates that both of these possibilities take place. That petitive loss of labeled and unlabeled HCN is still observed. is, scrambling and rearrangement processes combine with For metastable ions of benzimidazole, therefore, either the competitive fragmentation mechanisms for many of these benzimidazoles. rearrangement process results in specific partial scrambling of both carbon and hydrogen or competitive mechanisms exist Substituted Benzimidazoles. The 5(6)-substituted for fragmentation of the rearranged species. The latter has benzimidazoles and the two 1,3-diazaazulenes examined here been assumed to be the case by Maquestiau and co-workers are listed in Table I along with some important features of in their conclusion that the most reasonable common structure their mass spectral behavior. The inherent stability to fragfor fragmentation of benzimidazole, indazole, and o-aminomentation of this family of heteroaromatics is attested to by benzonitrile ions is through the latter structure with loss of the intensity of the parent ion peak which, for more than half the amine nitrogen and a ring carbon predominating. Our of the derivatives, is the base or most intense peak in the work with multiple labeling, Le., 2H in the 1 and 2 positions spectrum. In contrast to the fragmentation of benzimidazole, and 13C in the 2 position, clearly confirms competitive the parent ions of most derivatives do not lose HCN (column mechanisms for the metastable fragmentations. That is, losses four). In fact, the major fragmentation path in all cases (last of HCN, 2H1WN,and either or both 2HCN and H13CN exhibit column) involves initial loss of all or part of the substituent significant metastable peaks. Since rearrangement to a comrather than part of the benzimidazole nucleus. These initial mon structure is required by the 2H-labeling experin~ents,~ steps, then, should be observed generally with similarlycompetitive mechanisms for HCN loss from this structure substituted aromatic compounds, while later steps are unique must exist and partial, incomplete hydrogen scrambling is to the benzimidazoles. Three families of derivatives are evioccurring as required by loss of HCN from the trilabeled dent from the major pathways followed: (1) the alkyl derivabenzimidazole. tives fragmenting through a 131 ion; (2) those derivatives itive fragmentation mechanisms involved in HCN loss from benzimidazoles.
el. Org. Chem., Vol. 43, No. 18, 1978 3521
Mass Spectral Behavior of 5(6)-Substituted Benzimidazoles
Table 11. Deuterium and Carbon Isotope Ratios for the Competitive Loss of HCN/2HCN and HCN/H13CN, respectively, from Selected Ions a deuterium [m*(HCN)]'/ [ion - 2HCN]b/ [m * (ZHCNj] [ion - WCN]
benzimidazole substituent and ions H 119 (M+*) 118 (M+. - H.) 92 (M+*- HCN) 5(6)-C1 153 ( 3 5 ~ 1 - M+.) 126 (153 - HCN) 118 (M+*- C1) 91 (118 - HCN)
1.4d
1.011
carbon [ion - HCNIb/ [m*(HCN)Ic/ [ion - H13CN] [m*(H13CN)] 1.2
2.6 (1.8)
5
5(6)-NO2 118 (M+*- N02) 106 (M+. - NO - CO) 91 (118 - HCN) 5(6)-COCH3 118 (M+-- CH3 - CO) 91 (118 - HCN) 5(6)-CH3 132 (M+*- He) 105 (132 - HCN)
1.2 (0.3)
1.5 0.4
1.3
3.5
(1.1)
(0.7)
(0.7)
(0.3)
(0.4)
0.6 1.7 (2)
0.8
0.3
